COLORECTAL CANCER - MORPHOLOGY

SBALO – Angel MILEVUMBAL St. ANN – Stefan PETROV

07 – 11 - 2009

COLORECTAL CANCER - MORPHOLOGY

History says : In the beginning was Duke 1 and 2Afther that was Astler & Coller (Annals of Surgery, June, 1 9 5 4)

Astler & Coller RESULTS:

GROSS MORPHOLOGYColorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

Early carcinomas, i.e., tumors limited to the submucosa, are mostly

•polypoid

•pedunculated

• semipedunculated

• sessile

•flat lesions

•flat with slight elevation

•with light central depressionAdvanced carcinomas (invading beyond the submucosa) are four types, similar to the Borrmann categories of gastric carcinoma:

* Polypoid (protuberant) * Ulcerated, with sharply demarcated margins * Ulcerated without definite borders * Diffusely infiltrating

In contrast to gastric carcinomas, the latter two types are uncommon.The most common type is the ulcerated type with sharply demarcated margins.

GROSS MORPHOLOGYRosai and Ackerman’s SurgicalPathology, Juan Rosaj Edt., Vol. I, Mosby. (2004)

Advanced carcinomas (invading beyond

the submucosa) are four types, similar to the

Borrmann categories of gastric carcinoma:

* Polypoid (protuberant)





* Ulcerated, with sharply demarcated margins





* Ulcerated without definite borders





* Diffusely infiltrating

HISTOMORPHOLOGY - Histological TypingColorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

Extremely uncommon carcinomas not listed

in theWHO classification,

and reported in only a few cases, include

microglandular goblet cell carcinoma,

clear cell carcinoma, adenosquamous

carcinoma, spindle cell and

metaplastic carcinoma (carcinosarcoma),

giant cell carcinoma, choriocarcinoma,

carcinomas arising in endometriosis,

melanotic adenocarcinoma, and

Paneth cell rich papillary adenocarcinoma.

Pathology and Genetics of Tumours of the Digestive

System World Health Organization Classification of Tumours 2000 CRC - 1

ADENOCARCINOMA – GRADING – 1 – TO 3



MUCINOUS ADENOCARCINOMA



SIGNET RING-CELL CARCINOMA



PROGNOSTIC FACTORS IN CRC

HISTOMORPHOLOGY - Histological GradingColorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

Histopathological grading of tumors is performed to provide some indicationof their aggressiveness, which relates to prognosis and/or choice oftreatment. The traditional system of grading also used by the InternationalUnion Against Cancer (UICC) tumor node metastasis (TNM) classificationdistinguishes four grades: G1: well differentiated G2: moderately differentiated G3: poorly differentiated G4: undifferentiatedThe WHO provides and recommends a grading system with twoclasses: Low-grade, encompassing G1 and G2 High-grade, encompassing G3 and G4This latter grading system fulfills all clinical requirements, and can beperformed with higher reproducibility. We prefer this grading with onlytwo categories. When a carcinoma shows different grades of differentiation,the higher grade should determine the final categorization. Thus a carcinomathat shows both low- and high-grade areas should be classified as high-grade.However, the disorganized glands seen commonly at the advancing edge ofthe carcinoma should not be considered as high-grade malignancy. Highgradecarcinomas account for 20% to 25% of resected carcinomas.

HISTOMORPHOLOGY - Additional Histological ParametersColorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

The character of the invasive margin (pushing or expanding, orwell-circumscribed vs. irregular diffusely infiltrating) Peritumoral inflammation The presence of peritumorous lymphoid aggregates Invasion of lymphatic vessels (L classification): L0, no lymphaticinvasion, L1, lymphatic invasion; LX, lymphatic invasion cannot beassessed Venous invasion (V classification): V0, no venous invasion; V1,microscopic venous invasion; V2, macroscopic venous invasion;VX, venous invasion cannot be assessed. In case of microscopicvenous invasion, it is important to distinguish between involvementof intramural veins (submucosa, muscularis propria) and thatof extramural veins (beyond muscularis propria) Invasion of perineural spaces [Pn (perineural) classification]:Pn0, no perineural invasion, Pn1, perineural invasion; PnX,perineural invasion cannot be assessed.

SPECIAL CLINICAL TYPES OF COLORECTAL CANCER Colorecal

cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

• Hereditary Nonpolyposis Colon Cancer (HNPCC) - between 35 and 45 years), uncommon histological feature of medullary carcinoma (TILs), mucinous adenocarcinomas and high-grade tumors. An increased incidence of metachronous multiple primary tumors. HNPCC accounts for at least 4% to 6% of all colorectal carcinomas.

• Carcinoma Arising in Familial Adenomatous Polyposis (FAP) & (HFAS) -usually with fewer than 100 adenomas, mostly of the flat type. The histological features are similar to those of sporadic cancers. High proportion of multiple synchronous primary tumors in symptomatic cases (up to a third of cases).

• Carcinoma Developing in Inflammatory Bowel Disease - predominantly in extensive ulcerous colitis with a history of 10 years or longer, involving most of the large bowel (right-sided colitis) and with high activity of inflammation. Often synchronous multiple carcinomas. High-grade tumors, mucinous adenocarcinomas, and signet-ring cell carcinomas. Less than 1% of all colorectal carcinomas arise in inflammatory bowel disease.

TUMOR SPREAD IN COLORECTAL CARCINOMA Colorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

Cases of high-grade tumors, required a 2

cm distal resection margin.

The bidirectional lymph drainage of tumors

of thesplenic flexure and the

adjacent left third of the transverse colon

and upperthird of the descending

colon requires an extended left

hemicolectomy (leftand transverse colectomy) for

radical resection.

Colon Cancer, Adenocarcinoma: Differential Diagnoses & WorkupT Dragovich & VL Tsikitis Arizona Medical Center (2009)

If he has already acquired - 1

If he has already acquired - 2

causal treatment STAGING –pTNM & 5-year RELAPSE FREE SURVIVAL (short)

1 . pTNM STAGING

The UICCTNM/pTNM Classification of Tumors of the Colon and Rectum Colorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

T/pT—Primary tumorTX/pTX Primary tumor cannot be assessedT0/pT0 No evidence of primary tumorTis/pTis Carcinoma in situ: intraepithelial or invasion of

lamina propriaaT1/pT1 Tumor invades submucosaT2/pT2 Tumor invades muscularis propriaT3/pT3 Tumor invades through muscularis propria into

subserosa or into nonperitonealized pericolic or perirectal tissue

T4/pT4 Tumor directly invades other organs orstructuresb,c and/or perforates visceral peritoneumN/pN—Regional lymph nodesdNX/pNX Regional lymph nodes cannot be assessedN0/pN0 No regional lymph node metastasisN1/pN1 Metastasis in 1–3 pericolic or perirectal lymph

nodesN2/pN2 Metastasis in 4 or more pericolic or perirectal lymph

nodesM/pM—Distant metastasisMX/pMX Distant metastasis cannot be assessedM0/pM0 No distant metastasisM1/pM1 Distant metastasis

Regional lymph nodes for each anatomical site or subsite the following are regional: Appendix Ileocolic Cecum Ileocolic, right colic Ascending colon Ileocolic, right colic, middle colic Hepatic flexure Right colic, middle colic Transverse colon Right colic, middle colic, left colic, inferior mesenteric Splenic flexure Middle colic, left colic, inferior mesenteric Descending colon Left colic, inferior mesenteric Sigmoid colon Sigmoid, left colic, superior rectal (hemorrhoidal), inferior mesenteric, and rectosigmoid Rectum Superior, middle, and inferior rectal (hemorrhoidal), inferior mesenteric, internal iliac, mesorectal (paraproctal), lateral sacral, presacral, sacral promontory (Gerota)

(extended edition)

Ramifications (i.e., optional subdivisions of existing TNM/pTNM categories)

pT3

pT3a Minimal: tumor invades through the

muscularis propria into the subserosa or

into nonperitonealized pericolic or

perirectal tissues, not more than 1mm

beyond the outer border of the

muscularis propria

pT3b Slight: tumor invades through the muscularis

propria into the subserosa or into

nonperitonealized pericolic or perirectal

tissues, more than 1mm but not more than

5mm beyond the outer border of the

muscularis propria

pT3c Moderate: tumor invades through the


into nonperitonealized pericolic or perirectal

tissues, more than 5mm but not more than

15mm beyond the outer border of the

muscularis propria

pT3d Extensive: tumor invades through the


into nonperitonealized pericolic or perirectal

tissues, more than 15mm beyond outer

border of the muscularis propria

pT4

pT4a Invasion of adjacent organs or structures,

without perforation of the visceral peritoneum

pT4b Perforation of the visceral peritoneum

(extended edition)

The UICCTNM/pTNM Classification of Tumors of the Colon and Rectum Colorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007) (continued)

Note: The definitions of the clinical classification (TNM) correspond to those of the pathological classification (pTNM).

Stage grouping is shown in Figure 2.A This includes cancer cells confined within the

glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

B Direct invasion in T47pT4 includes invasion of other segments of the colorectum by way of the serosa, e.g., invasion of the sigmoid colon by a carcinoma of the cecum.

C Tumor that is adherent to other organs or structures, macroscopically, is classified as T4. However, if no tumor is present in the adhesion, microscopically, the classification should be pT3.

D A tumor nodule in the pericolic/perirectal adipose tissue without histological evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classifies in the T category and also coded as V1(microscopic venous invasion) or V2, if it was grossly evident, because there is a strong likelihood that it represents venous invasion.

Figure 2.

MALIGNANT TUMORS OTHER THAN CARCINOMAS Colorecal cancer / edited by Jim Cassidy, Patrick Johnston, Eric Van Cutsem. (2007)

Traditionally, neuroendocrine tumors have been separated from epithelial tumors and classified in a special way. They are classified as:

Well-differentiated neuroendocrine tumor (formerly: carcinoid), ICD-O code 8240/1

Well-differentiated neuroendocrine carcinoma (formerly: malignant carcinoid), ICD-O code 8240/3

Poorly differentiated neuroendocrine carcinoma (small cell carcinoma), ICD-O code 8041/3

GIST (1% of malignomas)

Kaposi sarcoma (AIDS?)

Primary malignant melanomas in the rectum (without involvement of the anal region)

Primary colorectal malignant lymphomas (involving the ileocecal region and the rectum)

The classification is not yet standardized

(for further details in noncarcinomatous

malignant tumors. ( ! )


System World Health Organization Classification of Tumours 2000 AC - 1

Anatomy of the anal canal



WHO histological classification of tumours of the anal canal (2000)



TNM classification of tumours of the anal canal (STAGING)

SQUAMOUS CELL CARCINOMA - PURE





SQUAMOUS CELL CARCINOMA – COMBINED



MUCINOUS ADENOCARCINOMA

>



ADENOCARCINOMA

MELANOMA MALIGNUM





PRECANCEROSES – HPV GENESIS



PRECANCEROSES – M. PAGET



Anal tumours - immunoreactivity profile

The results of our study – cecum, colon ascendens(1988 June – 2008 June incl. )

Мucinous

Ring-

Cell Аdeno-squamou

s

Squamo

us Small

cell Medulla

r Undifferentiated

Other Carcinoid

Mixed (carcinoid carcinoma)

MPC

19.444 0,128 0,256 0,512 - - 0,128 0,384 0,256 1,024 0,128

Fig. 1. Histological distribution of carcinomas(+ carcinoids) of 10 years period (1998-2008) - on

the operative material - "St.Ann" Hospital

19.444

00

0.1280.384 0.256

0.512

0.256

0.128

10.128 Мucinous

Ring-Cell

Аdeno-squamous

Squamous

Small cell

Medullar

Undifferentiated

Other

Carcinoid

Mixed carcinoid-carcinoma

MPC

The results of our study – MPC of colon ascendens - 1Fig. 2. MPC with chondroid ( C ) and osseous ( O ) metaplasia. Hematoxylin and Eosin. x 200.

Fig. 3 High Power view of chondroid metaplasia chondroid ( C ) with a close connection between that foci and the border of carcinoma’s glandule (BM – basement membrane - arrow). Hematoxylin and Eosin. x 400

The results of our study – MPC of colon ascendens - 2

Fig. 4 High Power view of osseous metaplasia ( O ) with a close connection between that foci and the border of carcinoma’s glandule (BM – basement membrane - arrow). Hematoxylin and Eosin. x 400

Fig. 5. Metastases of adenocarcinoma only in lymphatic nodule.Hematoxylin and Eosin. x 100

The results of our study – MPC of colon ascendens - 3Fig. 6. Diffuse ( 3 + )

Cytokeratin. Anti-Human Cytokeratin Clones AE1/AE3 (Dako), x 150

Fig. 7. Focal staining for Vimentin. Monoclonal Mouse Anti-Vimentin Clone VIM 3B4 (Dako), x 150

The results of our study – MPC of colon ascendens - 4Fig. 8. S-100 immunoreactivity

positive neuroendocrine cells and neuronal endings. Polyclonal Rabbit Anti-Cow S-100 (Dako), x 100

Fig. 9. VEGF (6p21,3) strongly positive in the stroma and perivascular. Monoclonal Mouse Anti-Human Vascular Endothelial Growth Factor Clone VG1 (Dako), x 200

The results of our study – MPC of colon ascendens - 5Fig. 10. α-SMA positive in

perineoplastic smooth muscle. Monoclonal Mouse Anti-Human Alpha Smooth Muscle Actin Clone 1A4 (Dako), x 200

Fig. 11. HER2 focal positive ( 2 + ). Polyclonal Rabbit Anti-Human c-erbB-2 Oncoprotein (Dako), x 150

The results of our study – MPC of colon ascendens - 6RESULTS Clinical Findings

The Patients ranged in age from 39 to 84 years were with an average age of 68. The Proportion between the men and women are 44.68% / 55.32% (all 77 patients) – all white. The local distribution of the tumors are as follows: 36 colon ascendens; 41 cecum. Matrix production of cartilaginous and osseous substance was found in only one case.

In the current study were found MPC in a white man at the age of 78. The Patient had right-sided hemicolectomy. No metastases were found out intraoperatively or by CAT.

Gross PathologyThe MPC tumor was with diameter of 10 cm. Macroscopically this nodular

protruded tumor had Invaded deep into the surrounding soft tissues. The Metastases were found in one of the two lymphonodules. No invasion was found in the resection borders and the omentum. Pathologically this case wasestimated as pTNM 9 : T3N1Mx.

HistopathologyMicroscopically (on the base of the histological estimation) we

found G2 – G3.Intestinal adenocarcinoma, in which, the most of the matrix foci

were of cartilaginous and osseous mature tissues. None of them reaches to the intestinal inner surface. In the high magnification ( x 40 ) we found out a close connection between that foci and the border of carcinoma’s glandule. These foci were located only in the carcinoma, and not in the metastase.

The results of our study – MPC of colon ascendens - 7DISCUSSION

This study describes a distinct subgroup of MPC of the human colon which hasn’t been described up till now.

In addition to the mayor criterion for a diagnosis of MPC, as follows:

the presence of overt carcinoma with direct transition to matrix-producing cells and cartilaginous / osseous matrix;

the matrix of MPC had to lack of intervening spindle cell or osteoclastic component (Wargotz, E.S, 1988), we propose to include the following:3. The foci of cartilage and osseous mature tissues in the matrix carcinoma must not reach the intestinal inner surface.4. They must be MULTIPLE.5. The MPC must be located only in the wall of the colon.

Cartilaginous and osseous metaplasia is an uncommon feature of tumors, arising in the human “overted” glands: mammary, salivary and others. They may occur in both: benign and malignant neoplasms.

In the colon they can be found in the so called “benign metaplastic polypus”, but their presence in malignant epithelial blastomas (carcinomas) was not recorded until now.

What’s next?Classification of colorectal cancer based on correlation of clinical,

morphological and molecular features.1. The Vienna classification of gastrointestinal epithelial neoplasia – Gut

2000;47;251-255, Dixon, P Sipponn, AN Price & HWatanabe, T Hirota, Y Kato et all. 48 pathologists from 15 countries reviewed a circulating slide set and attend this workshop on 5 and 6 September 1998 - Vienna, Austria.

In summary, this new classification is practicaland should be useful for

resolving many of thediscrepancies between Western and Japanese

pathologists in the diagnosis of

gastrointestinalepithelial neoplastic

lesions.

And the next? 1. Molecular Validation of the Modified Vienna Classification of Colorectal Tumors – Journal

of Molecular Diagnostics, Vol. 4, No. 4, November 2002, T Sugai, W Habano, N Uesugi, Yu-Fei Jiao,

Shin-ichi Nakamura, K Sato, T Chiba, and Motohiro Ishii. Iwate Medical University – Morioka – Japan.

Based on Crypt Isolation Method and DNA Extraction, Analysis of DNA Ploidy Pattern, Analysis of Allelic Imbalances at Chromosomal Loci and Analysis of Microsatellite Instability, using Polymerase Chain Reaction-Single-Strand Conformation Polymorphism Analysis and Sequencing,

COLORECTAL CANCER - MORPHOLOGY

SBALO – Angel MILEVUMBAL St. ANN – Stefan PETROV

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